Process for preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives, intermediates thereof and methods for their preparation

ABSTRACT

The invention relates to novel synthesis methods for the preparation of the intermediates, which are suitable for the preparation of statin derivatives, especially to novel synthesis methods of the intermediate of formula VI wherein R a ′ and R c ′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and R b  is a carboxy-protecting group, which methods are carried out by conversion of the intermediate of formula XVI wherein R a ′ and R c ′ are each independently of the other hydrogen or a hydroxy-protecting group, R* and R** are each independently of the other hydrogen or an amide-protecting group, and R b  is a carboxy-protecting group; which methods proceed to further new intermediates and methods for their preparation.

SUMMARY OF THE INVENTION

[0001] The invention relates to novel preparation processes for thepreparation of 3,5-dihydroxyheptanoic acid derivatives and to novelintermediates and processes for their preparation. Thedihydroxyheptanoic acid derivatives and the intermediates are suitablefor advantageous syntheses of statins.

BACKGROUND TO THE INVENTION

[0002] Statins are a class of pharmaceuticals that inhibit the enzymehydroxymethylglutaryl CoA reductase (HMG-CoA-R) and are therefore widelyused as hypolipidaemic agents and agents that lower the level ofcholesterol in the blood (hypocholesterollipidaemic agents). Allsynthetically prepared HMG-CoA-R inhibitors have, as common structuralfeatures, an aromatic base structure and the so-called statin sidechain, as symbolised by the following formula:

[0003] (wherein Aryl denotes aromatic, heterocyclic oraromatic-heterocyclic, unsubstituted or substituted, mono-, di- orpolycyclic ring systems). Such a structural unit can be found in a wholerange of pharmaceutically active agents, such as cerivastatin (BayerAG), fluvastatin (Novartis), itavastatin (NK-104; Kowa Company Ltd.),BMY 22089 (Bristol-Myers Squibb), rosuvastatin (S4522,AstraZeneca/Shionogi), glenvastin (Hoechst(Aventis) and atorvastatin(Warner-Lambert/Gödecke-Parke Davies/Pfizer).

[0004] The aim of the present invention is to provide new efficientmethods of synthesising some known statin derivatives and to provide newintermediate compounds.

GENERAL DESCRIPTION OF THE INVENTION

[0005] Key steps in the synthesis according to the invention are earlyintroduction of the correct absolute stereochemistry at C-3 (R) andsubsequent regioselective chain lengthening. Unlike the linear synthesisprocesses in the prior art, the use of the novel statin side chainbuilding blocks allows a convergent synthesis. The invention relatesalso to novel intermediates.

DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention concerns a process for the preparation ofthe intermediate of formula

[0007] wherein R_(a)′ and R_(c)′ are each independently of the otherhydrogen or a hydroxy-protecting group or together are a bridginghydroxy-protecting group, and R_(b) is a carboxy-protecting group, whichis suitable for the preparation of statin derivatives, which process iscarried out by conversion of the intermediate of formula XVI

[0008] wherein R_(a)′ and R_(c)′ are each independently of the otherhydrogen or a hydroxy-protecting group, R* and R** are eachindependently of the other hydrogen or an amide-protecting group, andR_(b) is a carboxy-protecting group; wherein compound of formula XVI isprepared by a process which comprises the preparation of a a compound offormula I

[0009] wherein X is halogen, acyloxy, activated hydrocarbyloxy,activated hydrocarbylthio or —N(CH₃)OCH₃, R_(a) is hydrogen or ahydroxy-protecting group and R_(b) is a carboxy-protecting group, whichintermediate converted into an amide of formula I*

[0010] wherein R_(c)′ is hydrogen or a hydroxy-protecting group, R_(b)′is hydrogen or a carboxy-protecting group and R* and R** are eachindependently of the other hydrogen or an amide-protecting group,preferably alkyl or substituted alkyl, more preferably C₁-C₄alkyl, suchas methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl,sec.-butyl, or substituted alkyl, such as benzyl, most preferablybenzyl, Which compound can then be converted for the preparation ofstatin precursors, especially those of formula VI already describedabove:

[0011] The conversion of compound of formula I* wherein R_(c)′ ishydrogen (obtainable, if necessary, from the compound of formula I*wherein R_(c)′ is a hydroxy-protecting group, by removal of protectinggroups) and R_(b)′, R* and R** are as defined for the compound offormula I*, preferably at least one of the radicals R* and R** being anamide-protecting group, is carried out by reaction in the presence of astrong base with a compound of formula XX

[0012] wherein R_(b) is a carboxy-protecting group, to form a compoundof formula XV

[0013] wherein R* and R** are as defined for compounds of formula I*,R_(c)′ is hydrogen and R_(b) is a carboxy-protecting group; thatcompound is then reduced diastereoselectively to form a syn-diol offormula XVI

[0014] wherein R_(a)′ and R_(a)′ are hydrogen; or, after subsequentintroduction of protecting groups, R_(a)′ and R_(a)′ are eachindependently of the other hydrogen or a hydroxy-protecting group, withthe proviso that at least one of the two radicals is such a protectinggroup, or R_(a)′ and R_(a)′ together are a bridging hydroxy-protectinggroup; R* and R** are as defined for the compound of formula I*,preferably at least one of them being an amide-protecting group; andR_(b) is a carboxy-protecting group; the resulting compound of formulaXVI is then converted into a compound of formula VI, as described above,by reduction and removal of protecting groups R* and R**, if present.

[0015] The invention relates also to a process for the preparation ofthe compound of formula I as defined above.

[0016] For that purpose, a compound of formula XI

[0017] wherein R_(a) is a hydroxy-protecting group (or, less preferredbecause the ee is then lower, hydrogen) and R_(b) is acarboxy-protecting group, is converted into the corresponding compoundof formula I using a reagent that introduces the radical X.

[0018] The compound of formula XI is in turn advantageously prepared byhydrolysing a compound of formula XII

[0019] wherein R_(a) is a hydroxy-protecting group (or, less preferredbecause the ee is then lower, hydrogen), R_(b) is a carboxy-protectinggroup and R_(d) is hydrocarbyl, by means of an enantio-selectivecatalyst (preferably by hydrolysis using a biocatalyst) with removal ofthe radical R_(d), the corresponding compound of formula XI beingobtained directly.

[0020] The compound of formula XII is advantageously obtained byreacting a glutaric acid derivative of formula XIII

[0021] wherein R_(b) and R_(d) are as defined for compounds of formulaXII, by introduction of a hydroxy-protecting group using thecorresponding reagent suitable for the introduction of the protectinggroup.

[0022] The invention relates also to new individual steps of theprocesses described above, to new combinations of individual steps andto new intermediate compounds.

[0023] Unless indicated to the contrary, the general terms (includingthe reactions and reaction conditions) used hereinabove and hereinbelowpreferably have the following meanings these specific definitions anddescriptions of reactions can be used independently of one anotherinstead of the general terms mentioned hereinabove and hereinbelow,resulting in preferred embodiments of the invention:

[0024] The prefix “-lower” or “lower” indicates that the radical inquestion contains preferably up to 7 carbon atoms, especially up to 4carbon atoms. Lower alkyl is therefore preferably C₁-C₇-alkyl,especially C₁-C₄alkyl, and may be unbranched or branched one or moretimes, insofar as possible. Unsaturated radicals, such as alkenyl oralkynyl, have at least two carbon atoms, preferably from 2 to 7,especially from 3 to 7, more especially 3 or 4.

[0025] In the processes mentioned hereinabove and hereinbelow, it ispossible at any stage, even where not explicitly mentioned, for one ormore or all of the protecting groups present in the compounds offormulae I to XIX in question to be removed or for one or more or all ofthe functional groups that are not to participate in the reaction, orthat would interfere with the reaction, to be converted into protectedgroups by the introduction of suitable protecting groups (especiallyhydroxy-protecting groups and/or carboxy-protecting groups).

[0026] The protection of functional groups by such protecting groups,suitable reagents for their introduction, suitable protecting groups andreactions for their removal will be familiar to the person skilled inthe art. Examples of suitable protecting groups can be found in standardworks, such as J. F. W. McOmie, “Protective Groups in OrganicChemistry”, Plenum Press, London and New York 1973, in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Meienhofer), Academic Press, London and New York 1981, in “Methodender organischen Chemie”, Houben-Weyl, 4^(th) edition, Vol. 15/l, GeorgThieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit,“Aminosauren, Peptide, Proteine”, Verlag Chemie, Weinheim, DeerfieldBeach, and Basel 1982, and/or in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide and Derivate”, Georg Thieme Verlag,Stuttgart 1974.

[0027] Suitable hydroxy-protecting groups are especially selected fromthose of the acyl or ester type, e.g. lower alkanoyl, such as formyl,acetyl or isobutyroyl, benzoylformyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,phenylacetyl, p-phenylacetyl, diphenylacetyl,2,6-dichloro-4-methylphenoxyacetyl,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetyl,2,4-bis(1,1-dimethylpropyl)phenoxyadetyl, chlorodipheny acetyl,3-phenylpropionyl, 4-azidobutyroyl, 4-methylthiomethoxybutyroyl,(E)-2-methyl-2-butenoyl, 4-nitro-4-methylpentanoyl, 4-pentenoyl,4-oxopentanoyl, 4,4-(ethylenedithio)-pentanoyl,5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy)laevulinyl, pivaloyl,crotonoyl, monosuccinoyl, benzoyl, p-phenylbenzoyl,2,4,6-trimethylbenzoyl, 2-(methylthiomethoxy-methyl)benzoyl,2-(chloroacetoxymethyl)benzoyl, 2-[(2-chloroacetoxy)ethyl]benzoyl,2-[(2-benzyloxy)ethyl]benzoyl, 2-[2-(4-methoxybenzyloxy)ethyl]benzoyl,2-iodobenzoyl, o-(di-bromomethyl)benzoyl, o-(methoxycarbonyl)benzoyl,2-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl,methoxymethylcarbonyl, 9-fluorenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl,1,1-dimethyl-2,2,2-trichloroethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)-ethoxycarbonyl,2-(triphenylphosphonio)ethoxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, p-nitrophenoxycarbonyl, benzyloxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxy-benzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,dansylethoxy-carbonyl, 2-(4-nitrophenyl)ethoxycarbonyl,2-(2,4-dinitrophenyl)ethoxycarbonyt, 2-cyano-1-phenylethoxycarbonyl,S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,3′,5′-dimethoxybenzoinyloxycarbonyl, 2-methylthiomethoxyethoxycarbonyl,N-phenylcarbamoyl, dimethylethylphosphinothiolyl, methyldithiocarbonyl;N,N,N′,N′-tetramethylphosphoro-diamidoyl, sulfonyl, methanesulfonyl,benzenesulfonyl, toluenesulfonyl, 2-[(4-nitrophenyl)-ethyl]sulfonyl,allylsulfonyl, 2-formylbenzenesulfonyl, nitroxy, or protecting groups ofthe ether type, such as methyl, substituted methyl, preferably loweralkoxymethyl, especially methoxymethyl (MOM), methylthiomethyl,(phenyldimethylsilyl)methoxymethyl, benzyloxymethyl,p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, gualacolmethyl,tert-butoxymethyl, 4-pentenyloxymethyl, silyloxymethyl, loweralkoxy-lower alkoxymethyl, especially 2-methoxyethoxymethyl (MEM),2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl ormenthoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 4-methoxythlopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydrothiopyranyl,S,S-dioxy-4-methoxytetrahydrothiopyranyl,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1-(2-fluorophenyl)-4-methoxypiperidinAyl, 1,4-dioxan-2-yl,tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl;substituted ethyl, such as 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl,1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl,1,1-dianisyl-2,2,2-trichloroethyl,1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl,2-benylthio)ethyl, 2-(phenylselenyl)ethyl, tert-butyl; allyl orpropargyl, substituted phenyl ethers, such as p-chlorophenyl,p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl or2,3,5,6-tetrafluoro-4-(trifluoromethyl)-phenyl, benzyl, substitutedbenzyl, such as p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, e.g. p-bromobenzyl, 2,6-dichlorobenzyl,p-cyanobenzyl, p-phenylbenzyl, 2,6-difluorobenzyl, p-azidobenzyl,4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl orp-(methylsulfinyl)benzyl, 2- or 4-picolyl, 3-methyl-2-picolyl,2-quinolinylmethyl, 1-pyrenylmethyl, diphenylmethyl,p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl),4,4′,4″-tris(laevulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,4,4′-dimethoxy-3″-[N-(imidazolylmethyl)]trityl,4,4′-dimethoxy-3″-[N-(imidazolylethyl)carbamoyl]trityl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,4-(17-tetrahydrobenzo[a,c,g,i]fluorenylmethyl)4′,4″-dimethoxytrityl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, S,S dioxo-benzoisothiazolyl; of the silylether-type, such as tri-lower alkylsilyl, e.g; trimethylsilyl;triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,diethylisopropylsilyl, dimethylthexylsilyl, tert-butyidimethylsilyl ordi-tert-butylmethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl,diphenylmethylsilyl, tris(trimethylsilyl)silyl,(2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)-diisopropylsilyl,tert-butylmethoxyphenylsilyl or tert-butoxydiphenylsilyl.

[0028] Bridging protecting groups can likewise be used where a moleculecontains two hydroxy groups (for example bridging hydroxy-protectinggroups formed by R_(a) and R_(b) or R_(a)′ and R_(a)′ together) or ahydroxy-protecting group and a carboxy group (for example bridgingprotecting groups formed by R_(a) and R_(b) or R_(a)′ and R_(b) in themolecules of the corresponding formulae mentioned hereinabove andhereinbelow in which those radicals are present).

[0029] A bridging hydroxy-protecting group (especially one formed byR_(a)′ and R_(a)′) is preferably selected from methylene, ethylidene,tert-butylmethylidene, 1-tert-butylethylidene, 1-phenylethylidene,1-(4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene,vinylmethylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene,benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene,3,4-dimethoxybenzylidene, 2-nitrobenzylidene, 4-nitrobenzylidene,mesitylene, phenyl-(1,2-bis(methylenyl)), methoxymethylene,ethoxymrethylene, dialkylsilylene, such as tert-butylsilylene,1,3-(1,1,3,3-tetraisopropyldisiloxanylidene),1,1,3,3-tetra-tert-butoxydisiloxanylidene, —C(═O)—,ethylboronyl(—(H₃CCH₂)B—), phenylboronyl (-(phenyl)B—),o-acetamidophenylboronyl or especially isopropylidene.

[0030] Carboxy-protecting groups are especially ester-forming,enzymatically and/or chemically removable protecting groups, preferablyenzymatically and/or chemically removable protecting groups, such asheptyl, 2-N-(morpholino)ethyl, cholinyl, methoxyethoxyethyl ormethoxyethyl; or those which are primarily chemically removable, e.g.alkyl, such as lower alkyl, especially methyl, ethyl, substituted loweralkyl (except for benzyl and substituted benzyl), such as substitutedmethyl, especially 9-fluorenylmethyl, methoxymethyl,methoxyethoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl,triisopropylsilylmethyl, 1,3-dithianyl-2-methyl, dicyclopropylmethyl,acetonyl, phenacyl, pbromophenacyl, α-methylphenacyl, p-methoxyphenacyl,desyl, carbamidomethyl, p-azobenzenecarboxamidomethyl,N-phthalimidomethyl or 4 picolyl, 2-substituted ethyl, especially2-iodo-, 2-bromo- or 2-chloro-ethyl, 2,2,2-trichloroethyl,2-(trimethylsilyl)ethyl, 2-methylthioethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)-ethyl,2-(2′-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,2-(4-acetyl-2-nitrophenyl)ethyl or 2-cyanoethyl, tert-butyl,3-methyl-3-pentyl, 2;4-dimethyl-3-pentyl or chloro lower alkyl,especially 4-chlorobutyl or 5-chloropentyl, cyclopentyl, cyclohexyl,lower alkenyl, especially allyl, methallyl, 2-methylbut-3-en-2-yl,3-methylbut-2-enyl or 3-buten-1-yl, substituted lower alkenyl,especially 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl orα-methylcinnamyl, lower alkynyl, such as prop-2-ynyl, phenyl,substituted phenyl, especially 2,6-dialkylphenyl, such as2,6-dimethylphenyl, 2,6-diisopropylphenyl,2,6-1-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl,p-(methylthio)-phenyl or pentafluorophenyl, benzyl, substituted benzyl,especially triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl,9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl,1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl,2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl,p-methoxybenzyl, 2,6-dimethoxybenzyl, 4 (methylsulfinyl)benzyl,4-sulfobenzyl, 4-azidomethoxybenzyl,4N-[1-(4,4-dimethyl-2,6-dioxocydohexylidene)methylbutyl]amino)benzyl,piperonyl or p-polymer-benzyl, tetrahydropyranyl, tetrahydrofuranyl, orsilyl radicals, such as tri-lower alkylsilyl, especially trimethylsilyl,triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl ordi-tert-butylmethylsilyl, or phenyl-di-lower alkylsilyl, such asphenyldimethylsilyl; alternatively a carboxy group can also be protectedin the form an oxazolyl, 2-alkyl-1,3-oxazolinyl,4-alkyl-5-oxo-1,3-oxazolidinyl or2,2-bistrifluoromethyl-4-alkyl-5-oxo-1,3-oxazolidinyl radical.

[0031] Amide-protecting groups are especially allyl, tert-butyl,N-methoxy, N-benzoyloxy, N-methylthio, triphenylmethylthio,tert-butyldimethylsilyl, triisopropylsilyl, 4-(methoxymethoxy)phenyl,2-methoxy-1-naphthyl, 9-fluorenyl, tert-butoxycarbonyl,N-benzyloxycarbonyl, N-methoxy- or N-ethoxy-carbonyl, toluenesulfonyl,N-buten-1-yl, 2-methoxycarbonylvinyl, or especially alkyl, such as loweralkyl, or more especially substituted alkyl, especially benzyl, benzylsubstituted by one or more radicals selected from lower alkoxy, such asmethoxy, lower alkanoyloxy, such as acetoxy, lower alkylsulfinyl, suchas methylsulfinyl, dicyclopropylmethyl, methoxymethyl, methylthiomethyland N-benzoyloxymethyl; or bis(trimethylsilyl)methyl,trichloroethoxymethyl, tert-butyidimethylsilyloxymethyl,pivaloyloxymethyl, cyanomethyl, benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl,o-nitrobenzyl, bis(4-methoxyphenyl)phenylmethyl,bis(4-methylsulfinylphenyl)methyl, pyrrolidinomethyl, diethoxymethyl,1-methoxy-2,2-dimethylpropyl or 2-(4-methylsulfonyl)ethyl.

[0032] It is characteristic of protecting groups that they are simple toremove (that is to say without undesirable secondary reactions takingplace), for example by solvolysis, reduction, photolysis oralternatively under conditions analogous to physiological conditions,for example enzymatically.

[0033] The person skilled in the art will know which protecting groupscan be used for which reactions and compounds of the present invention.Hydroxy-protecting groups R_(a) and R_(a)′ are especially those whichcan be selectively Introduced and removed, more especially those whichare not removed during the conversion of compounds of formula XII. Hereit is especially advisable to use hydroxy-protecting groups that do notcontain too strongly electronegative substituents, more especially loweralkanoyl, such as acetyl, lower alkoxy-lower alkanoyl, such asmethoxyacetyl, or protecting groups of the substituted methyl type,especially lower alkoxymethyl, more especially methoxymethyl (MOM), orlower alkoxy-lower alkoxymethyl, especially 2-methoxyethoxymethyl (MEM).

[0034] Acyloxy in formula I is especially the radical of an organiccarboxylic or sulfonic acid having from 1 to 24 carbon atoms,unsubstituted or substituted by one or more radicals, especially from 1to 3 radicals, preferably selected from lower alkoxy, halogen, nitro,lower alkoxycarbonyl, phenyl, phenyl-lower alkyl, phenyloxy, loweralkanoyloxy, benzoyloxy, di-lower alkyl-amino, N-phenyl-loweralkyl-N-lower alkyl-amino, N,N-di(phenyl-lower alkyl)-amino, carbamoyl,thiocarbamoyl, sulfamoyl and cyano, and saturated or partially or fullyunsaturated, and is preferably the radical of an alkanecarboxylic acidor haloalkanecarboxylic acid, especially lower alkanoyl, of anarylcarboxylic acid, especially benzoic acid, or halo-loweralkanesulfonyl, such as trifluoromethanesulfonyl; or, in the case of acompound of formula I, a radical of formula I′

[0035] wherein R_(a) and R_(b) are as defined for compounds of formula I(the compound of formula I is then a symmetric anhydride (obtainable,for example, by reaction of the acid of formula I (OH instead of X) inthe presence of a lower alkanecarboxylic acid anhydride, such as aceticanhydride, in the presence of catalytic amounts of acid)).

[0036] Activated hydrocarbyloxy or hydrocarbytthio is preferablyunsubstituted or substituted lower alkyloxy, unsubstituted orsubstituted aryloxy (preferably having from 6 to 12 ring atoms) orunsubstituted or substituted heterocycyloxy (preferably an unsaturated,fully or partially saturated mono- or biyclic ring system having from 4to 12 ring atoms and up to three hetero atoms selected from nitrogen,sulfur and oxygen) and is especially lower alkyloxy substituted in the1-position by esterified carbonyl, such as lower alkoxycarbonyl, cyanoor by phenylcarbonyl, especially lower alkoxycarbonylmethoxy, such asethoxycarbonylmethoxy, cyanomethoxy or phenacyloxy(Ph—CO—CH₂—O—),tert-butylthio, N-benzotriazolyloxy, N-succinimidyloxy, pyridyloxy orpyridylthio, especially 2-pyridyloxy or more especially 2-pyridylthio,or electronegatively substituted aryloxy, such as p-nitrophehyloxy,2,4-dinitrophenyloxy, pentafluorophenyloxy or 2,4,5-trichlorophenyloxy.

[0037] Any hydroxy-protecting groups R_(a) can then, if necessary, beremoved selectively, especially by the methods described in the standardworks mentioned above.

[0038] “Selectively” means especially enzymatcally. In particular, loweralkanoyl, such as acetyl, is removed enzymatically, for example byesterases, such as pig's liver esterase, in suitable buffers, such asphosphate buffer, at preferred pH values of from 5 to 9, especially from6 to 8. Further possible enzymes and reaction conditions will be foundbelow under the definition of biocatalysts for the hydrolysis. Loweralkoxymethyl, such as MOM, or lower alkoxy-lower alkoxymethyl, such asMEM, is removed by chemical standard methods.

[0039] The diastereoselective reduction of a compound of formula XV(when R_(c)′ is a hydroxy-protecting group, after removal thereof) toform a compound of formula XVI in each case as defined above and below,is then preferably carried out in a chelate-controlled manner, therebeing used as chelate-forming agent preferably a di-lower alkyl borinicacid lower alkyl ester or mixtures of triethylborane or diethylboranemethoxide with sodium borhydride, especially diethyl borinic acid ethylester. As solvent there are preferably used ethers, such as cyclicethers, especially tetrahydrofuran, and/or alcohols, such as loweralkanols, e.g. methanol, or mixtures of them, preferred is a mixture oftetrahydrofuran and methanol; the preferred reaction temperatures beingfrom −80 to −30° C., especially from −78 to 40° C.

[0040] Further, preferred is the diasteroselective reduction of compoundof formula XV to XVI with hydrogen In the presence of a homogeneousmetal catalyst. Customary, the reduction is carried out in the presenceof an organic solvent. Preferred metal of the homogeneous metal catalystis a metal of Group VII of the periodic table of elements. Morepreferred is a ruthenium catalyst, for the reaction with a rutheniumcatalyst and hydrogen the preferred reaction temperatures being from 0to 150° C. under pressure of 1 to 100 bar, preferably from 10 to 60° C.under pressure of 10 to 60 bar.

[0041] In addition, preferred is the diasteroselective reduction ofcompound of formula XV to XVI with hydrogen in the presence of an alkalimetal salt or alkaline-earth metal salt and a heterogeneous platinumcatalyst. Preferred salt is an alkaline-earth metal salt most preferredis a magnesium salt, and especially preferred is magnesium acetate.Customary this diasteroselective reduction is carried under pressurebetween 1 to 100 bar at temperatures between 0 to 100° C. Mostpreferably the reduction is carried out using a platinum on carboncatalyst together with magnesium acetate with hydrogen under a pressureof 6 to 60 bar at temperatures between 10 to 60° C.

[0042] In a broader embodiment of the invention it is also preferred touse alternative reducing agents, such as sodium cyanoborohydride, butthis results in lower diastereoselectivity and is therefore lesspreferred.

[0043] The bridging protecting group formed by R_(a)′ and R_(c)′together, preferably as indicated above, especially the isopropylideneprotecting group, is especially introduced by standard methods,preferably as described in the standard works mentioned above, in thecase of the isopropylidene protecting group especially by reaction withacetone or, preferably, with a dilower alkoxypropane, such asdimethoxypropane, in the presence of copper(II)sulfate, zinc chlorideor, preferably, an acid, such as sulfuric acid or especially an organicsulfonic acid, such as an arylsulfonic acid (wherein aryl has especiallyfrom 6 to 10 ring atoms, e.g. naphthyl or phenyl, and is unsubstitutedor mono- or poly-substituted, especially up to trisubstituted,especially by lower alkyl, such as methyl), preferably toluenesulfonicacid, or with a lower alkyl isopropenyl ether, such as ethyl isopropenylether, in the presence of an arylsulfonic acid. As preferred solventsthere are used aprotic solvents, such as ethers, especially cyclicethers, more especially tetrahydrofuran, or carboxylic acid amides, suchas di-lower alkyl-lower alkanoylamides, e.g. dimethylformamide. Thepreferred reaction temperatures are in the range of from 0 to 80° C.,especially from 20 to 30° C.

[0044] The reaction for the preparation of a compound of formula XI toform the corresponding compound of formula I is preferably effectedunder customary conditions, there being used as reagent for introducinga radical X especially an acid anhydride or an acid halide, preferablyan inorganic acid halide, more especially a phosphorus trihalide,phosphorus pentahalide or thionyl halide, such as phosphoryl chloride,phosphoryl bromide, phosphorus trichloride, phosphorus tribromide,phosphorus pentachloride, phosphorus pentabromide, thionyl chloride orthionyl bromide, a symmetric anhydride of a lower alkanesulfonic acidhalogenated at the α-carbon atom, such as trifluoromethanesulfonicanhydride, or an acid chloride or a symmetric anhydride of an organiccarboxylic acid, especially an oxalyl halide, such as oxalyl chloride orbromide, the reaction being carried out in the absence or preferablypresence of a (preferably polar) solvent or solvent mixture, especiallyin a halogenated hydrocarbon, preferably methylene chloride, in theabsence or presence of an acid amide, especially a di-lower alkyl-loweralkanoic acid amide, such as dimethylformamide, at preferredtemperatures of from −20° C. to the reflux temperature of the reactionmixture in question, preferably from −10 to 50° C.

[0045] Hydrocarbyl R_(d) in a compound of formula XII is preferably asaturated, fully or partially unsaturated, cyclic (having one or more,especially up to three, fused rings), linear, branched or mixedcyclic-linear or cyclic-branched hydrocarbon radical having up to 24carbon atoms, preferably up to 10 carbon atoms, especially lower alkyl,and is unsubstituted or mono- or poly-substituted, preferably up totri-substituted, especially by hydroxy, lower alkoxy, phenyl-loweralkoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, benzoyloxy,halogen, carboxy, lower alkoxycarbonyl or halo-lower alkyl, such astrifluoromethyl. Preference is given to lower alkyl, especially methylor more especially ethyl, or lower alkoxy-lower alkyl, especiallymethoxymethyl. Preferably, in the compounds of formulae XII and XIII thecarboxy-protecting group R_(b) is identical to the hydrocarbyl groupR_(d), especially in each case lower alkyl, more especially methyl orethyl, branched lower alkyl or lower alkoxy-lower alkyl, especiallymethoxymethyl.

[0046] The preparation of a compound of formula XI is preferablyeffected with removal of the hydrocarbyl radical R_(d) in the presenceof an enantioselective catalyst, especially a biocatalyst.

[0047] As biocatalysts for the hydrolysis there are suitable cells orruptured cells with the enzymes mentioned below, or especially enzymesas such, preferably esterases, lipases and proteases (peptidases oramidases, see U. T. Bomscheuer and R. T. Kazlauskas, in: Hydrolases inOrganic Synthesis, Wiley-VCH, 1999, pages 65195, ISBN 3-527-301046).Common representatives of those classes of enzyme are especially animalesterases (e.g. pig's liver esterase=PLE, pig's pancreas esterase=PPL),esterases from microorganisms or fungi (B. subtilis esterase, Pichiaesterases, yeast esterases, Rhizopus sp. esterases (RML, ROL),Penicillium sp. esterases, G. candidum (GCL), H. lanuginosa (HLL),Candida sp. (CAL-A, CAL-B, CCL), Aspergillus sp. (ANL), Pseudomonas sp.(PCL, PFL) and the like), and also proteases, e.g. subtilisin,thermitase, chymotrypsin, thermolysin, papain, aminoacylases, penicillinamidases, trypsin or the like, to name only a few. The person skilled inthe art will be familiar with further suitable enzymes, and the enzymesthat can be used are not limited to those mentioned in the above list.Such enzymes can be obtained in the form of crude isolates and/or inpurified form from natural sources and/or from recombinantmicroorganisms by means of modern cloning procedures via overexpression,amplification or the like. Commercially available enzymes are especiallypreferred. The enzymes can be present as such or immobilised or adsorbedon carriers, for example on silica gel, kieselguhr, such as Celite®,Eupergit® (Röhm & Haas, Darmstadt, Germany) or the like, or used in theform of “CLECs” (cross-linked enzymes), such as are available from ALTUSBIOLOGICS, the scope for use extending beyond the list given, as theperson skilled in the art will know (see U. T. Bomscheuer and R. T.Kazlauskas, in: Hydrolases in Organic Synthesis,) Wiley-VCH, 1999, pages61-64, ISBN 3-527-30104-6; K Faber in: Biotransformation in OrganicChemistry, Springer 1997, Third Edition, pages 345-357, ISBN3-54061688-8; H. J. Rehm, G. Reed in: Biotechnology, VCH 1998, SecondEdition, pages 407-411). The enzymes can be used in pure organicsolvents, e.g. liquid hydrocarbons, such as hexane, toluene or benzene,liquid ethers, such as diethyl ether, methyl tert-butyl ether ortetrahydrofuran, liquid halogenated hydrocarbons, such as methylenechloride, water or aqueous buffer solutions, in mixtures of thosesolvents, for example mixtures of one or more thereof with water oraqueous buffer solutions. The aqueous solution is preferably buffered,pH 5-9, it being possible to use customary buffer systems (see e.g. K.Faber in: Biotransformation in Organic Chemistry, Springer 1997, ThirdEdition, p. 305; or U. T. Bornscheuer and R. T. Kazlauskas, in:Hydrolases in Organic Synthesis, Wiley-VCH, 1999, pages 61-65). The pHis preferably kept substantially constant during the reaction. Mostsuitable for this purpose is an automatic titrator having a standardisedacid or base solution, or manual titration. The reaction temperature ispreferably in the range from 10 to 50° C., especially from 25 to 40° C.The amount of biocatlyst used and the concentrations of the reagents canbe dependent upon the substrate and the reaction conditions(temperature, solvent etc.) selected in each case, as will be known tothe person skilled in the art There are preferably used commerciallyavailable enzymes (for example from Fluka, Sigma, Novo Nordisk, Amano,Roche and the like) or those listed in the current literature (see e.g.H.-J. Rehm, G. Reed in: Biotechnology, VCH 1998, 2^(nd) Edition, pages40-42). Especially preferred for the preparation of enantiomericallypure compounds is o-chymotrypsin in phosphate buffer, especially at pH7.0.

[0048] The preparation of an amide of formula I* from a compound offormula I is carried out under customary conditions for the introductionof ammonia or amines and, where applicable, amide-protecting groups. Forexample, for the introduction of —NH₂ (R*═R**═H) reaction with ammoniais carried out, preferably in a suitable solvent, such as an ether, e.g.a di-lower alkyl ether, such as tert-butyl methyl ether, at preferredtemperatures of from −20 to 30° C., e.g. at 0° C. For the introductionof substituted alkyl radicals (especially R*═R**=benzyl), reaction withthe corresponding amine (e.g. dibenzylamine) is carried out in thepresence of a tertiary nitrogen base, such as a tri-lower alkylamine orpyridine, dimethylaminopyridine or the like, in a suitable solvent, suchas a halogenated hydrocarbon, e.g. methylene chloride, at preferredtemperatures of from −20 to 30° C., especially at approximately 0° C.

[0049] The introduction of protecting groups into compounds of formulaXVI is carried out, if necessary, in accordance with standard methods,especially as described in the standard works mentioned.

[0050] The dehydration of a compound of formula I* wherein R* and R**are each hydrogen, R_(b)′ is a carboxy-protecting group and R_(c)′ is ahydroxy-protecting group is carried out in the presence of suitabledehydrating agents, such as phosphorus(V)oxide or phosphoryl chloride atelevated temperatures, or with cyanuric chloride, in an aprotic solvent,especially an ether, such as a lower alkane-lower alkyl ether, e.g.tert-butyl methyl ether, and/or an acid amide, especially anN,N-di-lower alkyl-lower alkanoylamide, such as dimethylformamide, atpreferred temperatures of from 10° C. to the reflux temperature, forexample from 20 to 30° C.

[0051] The reduction and removal of protecting groups from an amidecompound of formula XVI for conversion into a compound of formula VI iscarried out under standard conditions using suitable reducing agents,such as hydrogenating agents or hydrogen; for example by initialtreatment with a hydride, such as borane, in a customary solvent,especially a solvent that stabilises the reducing agent, such as acyclic ether, such as tetrahydrofuran, at preferred temperatures of from0 to 60° C., especially from 30 to 50° C., and subsequent hydrogenationin the presence of a transition metal catalyst, especially a noble metalcatalyst, such as platinum or palladium, in each case preferably boundto a carrier, especially carbon, in a suitable solvent, preferably analcohol, such as ethanol, especially under normal pressure or elevatedhydrogen pressure, for example at from 1 to 30 bar (especially for R*and R**=each benzyl).

[0052] Unless otherwise indicated, halogen is preferably fluorine,chlorine, bromine or iodine, more preferred is chlorine.

[0053] Wherever solvents are mentioned hereinabove and hereinbelow it isalso possible, where expedient and possible, for mixtures of two or moreof the mentioned solvents to be used. The person skilled in the art willknow that for certain reactions such solvents or solvent mixtures mustbe used in anhydrous (absolute) form and that, if necessary, also thereaction vessels used must have dry surfaces.

[0054] Where necessary, the said reactions are carried out in theabsence of oxygen, and often also in the absence of carbon dioxideand/or atmospheric moisture, for example under protective gas, such asargon or nitrogen.

[0055] Where possible, the starting compounds and intermediate compoundscan also be used in the form of salts, obtained in the form of salts orconverted into salts in accordance with customary processes, for examplein the case of carboxy compounds into the corresponding metal salts,such as alkali metal salts, e.g. sodium or potassium salts, or alkalineearth metal salts, such as calcium salts, or salts with nitrogen bases,such as ammonium, tri-lower alkylammonium, pyridinium salts or the like.Where salt formation is possible, any reference to any of the compoundsshould be understood as also including the corresponding salts.

[0056] In addition to the solvents already mentioned, it is alsopossible to use other suitable solvents, where expedient and possiblefor the reaction in question. Such solvents can be selected, forexample, from the following list water, esters, e.g. lower alkyl-loweralkanoates, such as diethyl acetate, ethers, e.g. aliphatic ethers, suchas diethyl ether, or cyclic ethers, such as dioxane or tetrahydrofuran,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as dichloromethane,chloroform or ethylene chloride, acid amides, such as dimethylformamide,bases, e.g. heterocyclic nitrogen bases, such as pyridine, carboxylicacids, such as lower alkanecarboxylic acids, e.g. acetic acid,carboxylic acid anhydrides, e.g. lower alkanoic acid anhydrides, e.g.acetic anhydride, cyclic, linear or branched hydrocarbons, such ascydohexane, hexane or isopentane, or mixtures of such solvents or othersolvents, e.g. aqueous solutions. Such solvents and solvent mixtures canalso be used in working-up, e.g. by chromatography or partition. Anymention of solvents or eluants hereinabove and hereinbelow should beunderstood as including also mixtures of such solvents or eluants.

[0057] The other compounds, especially of formula XX, are known, can beprepared according to methods known per se and/or are commerciallyavailable.

PREFERRED EMBODIMENTS OF THE INVENTION

[0058] Preferred aspects of the invention can be found in the claims,which are incorporated herein by reference.

[0059] Hereinabove and hereinbelow, the radicals in compounds of theformulae of the present invention have the meanings given hereinaboveand hereinbelow (especially the specific meanings mentioned for certainreaction variants or methods), and the reaction conditions are in eachcase as defined hereinabove or hereinbelow, preferably as the preferredreaction conditions:

[0060] Preference is given to a process for the preparation of statinderivatives which comprises the preparation of a compound of formula I,as defined hereinabove and hereinbelow, from a compound of formula XI,preferably such a process for the preparation of a compound of formulaI; the compound of formula XI in turn preferably being prepared from acompound of formula XII which, in turn, is preferably prepared from acompound of formula XIII.

[0061] Preference is given to a process for the preparation of statinderivatives, especially of formula VI, comprising initially theconversion of the compound of formula I into a compound of formula I*;then preferably reaction thereof with a compound of formula XX to form acompound of formula XV; then preferably conversion thereof into acompound of formula XVI; and finally preferably reduction of the latterto form a compound of formula VI.

[0062] In all the preferred embodiments, if necessary one or more or allof the protecting groups present are removed or one or more or all ofthe functional groups that are not to participate in a reaction, or thatwould interfere with the reaction, are converted into protected groupsby the introduction of suitable protecting groups (especiallyhydroxy-protecting groups and/or carboxy-protecting groups); and, wheresalt-forming groups are present and the reaction in question is notimpaired, the compounds of the present invention may also be in saltform.

[0063] A further embodiment of the present invention concerns the use ofthe compounds and processes of any of the preceeding claims for thepreparation of a compound of formula VI.

[0064] In addition, the present invention relates to the use of acompound of formula VI for the preparation of Atorvastatin®.Atorvastatin® is commercially available, such as fromWarner-Lambert/Gödecke-Parke Davies/Pfizer.

[0065] Of the compounds, the invention relates especially to those offormulae I, I*, VI, XV and XVI as such, especially those in which thesubstituents correspond to the radicals indicated in the respectiveExamples.

[0066] Special preference is given to the compounds 1d, 1e, 11a, 11b,11c, 12a, 13a, 13b and Bb mentioned in the Examples, especially eachindividual compound.

[0067] The present invention relates especially to the reaction stepsand new intermediate compounds mentioned in the following Examples.

EXAMPLES

[0068] The following Examples serve to illustrate the invention but donot limit the scope thereof.

[0069] Abbreviations used:

[0070] Celite Celite®, filtration aid based on kieselguhr, trade mark ofCelite Corp., USA

[0071] TLC thin-layer chromatography

[0072] DMF dimethylformamide

[0073] eq. equivalent

[0074] h hour(s)

[0075] Hünig's base N-ethyldiisopropylamine

[0076] min minute(s)

[0077] NMR nuclear magnetic resonance spectroscopy

[0078] PLE pig's liver esterase

[0079] m.p. melting point (° C.)

[0080] THF tetrahydrofuran

[0081] torr unit of pressure (mm mercury column); 1 torr corresponds to0.1333 kPa

[0082] Unless otherwise indicated, the ratios of the components ofeluant mixtures, solvent mixtures and the like are given in parts byvolume (v/v).

[0083] Reaction Scheme I for Examples 1 to 4:

EXAMPLE 1

[0084] a) Precursor of Formula Ba wherein R=ethyl.A=acetyl(diethyl-3-acetoxyalutaric Acid):

[0085] 54.0 g of diethyl-hydroxyglutaric acid (Fluka, Buchs,Switzerland) are dissolved at room temperature In 26.5 ml of pyridineand 27.4 ml of acetic anhydride and the mixture is stirred for about 12h until all the starting material has reacted. The mixture is dilutedwith ethyl acetate and washed in succession with water, 1N hydrochloricacid, saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. The organic phase is separated and dried overmagnesium sulfate. After evaporation of the organic solvent, 64.3 g ofNMR-spectroscopically pure acetate, the title compound, remain: ¹H-NMR(CDCl₃): 1.24 (t, 6H); 2.01 (s, 3H); 2.69 (d, 4H); 4.14 (q, 4H); 5.50(quin., 1H).

[0086] b) Compound of formula Ca wherein R=ethyl.A=acetyl(monoethyl-3(R)-acetoxyglutaric Acid):

[0087] 160 g of diethyl-3-acetoxyglutaric acid Ba are suspended at roomtemperature in 570 ml of distilled water, and 168 ml of 0.1M phosphatebuffer (pH 7) are added. After the addition of 2.7 g of achymotrypsin(Sigma, Sigma Chemie, Buchs, Switzerland), the mixture is stirredvigorously and maintained at pH 7.8 using a pH meter and pH stat(Metrohm) and 0.5N sodium hydroxide solution. When the theoreticalamount of hydroxide solution (1.3 litres) has been consumed, the mixtureis extracted with ethyl acetate. The aqueous phase is adjusted to pH 1with concentrated hydrochloric acid (conc. HCl) and then extracted withethyl acetate. Any cloudiness of the organic phase can be removed byfiltration over Celite. After evaporation of the organic phase, 131 g(97%) of semi-ester Ca remain: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.03 (s,3H); 2.71 (d, 2H); 2.77 (d, 2H); 4.14 (q, 2H); 5.50 (quin., 1H).

[0088] c) Determination of the Enantiomeric Excess (ee) of the MonoacidCa by Means of the Amide Da (R=ethyl, A=acetyl):

[0089] 150 mg of the monoacid Ca are reacted in accordance with thecustomary methods of peptide coupling with 341 mg of(benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 246 mg of Hünig's base and 93 μl ofR-phenylethylamine (Fluka, Buchs, Switzerland) in 1.5 ml of DMF at roomtemperature. After customary extraction, 188 mg of amide Da areobtained. NMR spectroscopy indicates a diastereoisomeric ratio of 99:1on the basis of the shift difference between the two diastereoisomericacetates and accordingly a ratio of R to S of 99:1. HPLC analysis(column: Chiracel OJ 25 cm×0.46 cm (Daicel Chemical Industries, Ltd.,JP), n-hexane:ethanol=95:5, flow rate 1.2 ml/min, UV detection at 210nm) confirms the ratio of R to S as 98.8: 1.2. ¹H-NMR (CDCl₃): 1.15 (t,3H); 1.35 (d, 3H); 1.85 and 1.87 (2×s, total 3H, ratio as 99:1); 2.47(m, 2H); 2.55 (dd, 1H); 2.65 (d, 1H); 4.01 (broad q, 1H); 5.00 (quint,1H); 5.38 (m, 1H); 6.51 (broad d, NH); 7.20 (m, 5H).

EXAMPLE 2

[0090] a) Precursor of Formula Bb wherein R=ethyl,A=Methoxyacetyl(diethyl-3-methoxyacetoxyglutaric Acid):

[0091] 50.0 g of diethyl-3-hydroxyglutaric acid (Fluka, Buchs,Switzerland) are dissolved at 0° C. in 80 ml of dichloromethane; 20.6 mlof pyridine and 22.9 ml of methoxyacetyl chloride are added and themixture is stirred at room temperature for about 12 h until all thestarting material has reacted. The mixture is washed in succession withwater, 1N hydrochloric acid, saturated sodium hydrogen carbonatesolution and saturated sodium chloride solution. The organic phase isseparated and dried over magnesium sulfate. After evaporation of theorganic solvent, a dark-yellow syrup is obtained which is filtered overa small amount of silica gel using hexane/ethyl acetate (2:1). Afterevaporation of the solvent, 65.0 g of NMR-spectroscopically puremethoxyacetate Bb are obtained: ¹H-NMR (CDCl₃): 1.20 (t, 3H); 2.65 (d,4H); 3.35 (s, 3H); 3.90 (s, 2H); 4.04 (q, 4H); 5.55 (quin., 1H).

[0092] b) Compound of Formula Cb wherein R=Ethyl,A=Methoxyacetyl(monoethyl-3(R)-methoxyacetoxyglutaric Acid):

[0093] 40.0 g of diethyl-3-methoxyacetoxyglutaric acid Bb are suspendedat room temperature in 150 ml of distilled water, and 43 ml of 0.1Mphosphate buffer (pH 7) are added. After the addition of 0.4 g ofα-chymotrypsin (Sigma; Sigma Chemie, Buchs, Switzerland), the mixture isstirred vigorously and maintained at pH 7.8 using a pH meter and pH stat(Metrohm) and 0.5N sodium hydroxide solution. After 18 h, a further 0.1g of chymotrypsin is added and stirring is continued unto thetheoretical amount of hydroxide solution has been consumed. The mixtureis then extracted with ethyl acetate (4×). The aqueous phase is adjustedto pH 1 with concentrated hydrochloric acid (conc. HCl) and thenextracted with ethyl acetate. Any cloudiness of the organic phase can beremoved by filtration over Celite. After evaporation of the organicphase, 24.8 g of semi-ester Cb remain: ¹H-NMR (CDCl₃): 1.24 (t, 3H);2.74 (d, 2H); 2.75 (d, 2H); 3.42 (s, 3H); 3.99 (s, 2H); 4.14 (q, 2H);5.59 (quin., 1H).

[0094] Alternatively, immobilised chymotrypsin can also advantageouslybe used. It can be supported on silica gel (Sigma SO₅₀₇, 230-400 mesh,average pore diameter 0.6 nm; Sigma Chemie, Buchs, Switzerland) bycustomary methods without loss of activity, easily removed and then usedrepeatedly.

[0095] c) Determination of the Enantiomeric Excess (ee) of the MonoacidCb by Means of Benzamide Db (R=Ethyl, A=Methoxyacetyl):

[0096] 200 mg of the monoacid Cb are reacted by customary methods ofpeptide coupling with 392 mg of(benzotriazol-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 290 μl of Hünig's base and 88 μl of benzylamine(Fluka, Buchs, Switzerland) in 2.0 ml of DMF at room temperature. Aftercustomary extraction, 178 mg of amide Db are obtained. HPLC analysis(Chiracel OD 25 cm×0.46 cm (Daicel Chemical Industries, Ltd., JP),n-hexane:ethanol=9:1, flow rate 1 ml/min, UV detection at 210 nm) yieldsa ratio of R to S of 98.6: 1.4. ¹H-NMR (CDCl₃): 1.22 (t, I=7.0, 3H);2.62 (d, I=6.5, 2H); 2.75 (dd, I=15.8, 5.3, 2H); 3.35 (s, 3H); 3.91 (s,2H); 4.10 (q, I=7.0, 2H); 4.38 (d, I=5.9, 2H); 5.56-5.65 (m, 1H); 6.31(t, br, NH); 7.21-7.33 (m, 5H).

[0097] d) Purification of the Compound Cb wherein R=Ethyl,A=Methoxyacetyl(monoethyl-3(R)-methoxyacetoxyplutaric Acid):

[0098] 500 g of monoacid Cb are dissolved in 2 litres of tert-butylmethyl ether and heated to boiling. 400 ml (1 eq.) of dicyclohexylaminedissolved in 2 litres of tert-butyl methyl ether are added dropwise inthe course of 10 min, followed by 4 litres of n-hexane. Ifcrystallisation does not start spontaneously, seeding is carried out,followed by cooling to 5-10° C. The resulting crystals are filtered offwith suction and dried in vacuo at 70° C. Yield: 694 g, 80% whitecrystals, m.p.=111° C. 3 g of the resulting salt are dissolved in 20 mlof water, NaCl is added to the solution and 1 eq. of 3N hydrochloricacid is added. The precipitated dicyclohexylamine hydrochloride isfiltered off with suction and the clear filtrate is extracted repeatedlywith tert-butyl methyl ether. After drying and removal of the solvent,1.6 g, 92%, of monoacid Cb are obtained; ee≧99.5%, determined by way ofthe benzamide analogously to c).

EXAMPLE 3

[0099] a) Precursor of Formula Bc wherein R=Ethyl,A=Methoxymethyl(diethyl-3-methoxymethoxyglutaric Acid):

[0100] 97.2 g of diethyl-3-hydroxyglutaric acid A (Fluka) are dissolvedat 0° C. together with 210 ml of formaldehyde dimethylacetal in 350 mlof dichloromethane, and 61.3 g of phosphorus pentoxide are added inportions. The mixture is stirred vigorously overnight, the temperatureof the mixture rising to room temperature. When conversion is complete(TLC monitoring), the mixture is decanted off, diluted with methylenechloride and washed in succession with 2×saturated sodium hydrogencarbonate solution and saturated sodium chloride solution. The organicphase is separated and dried over magnesium sulfate. After evaporationof the solvent, a colourless fluid is obtained which is distilled at98-101° C./0.17 torr. 104.8 g (89%) of a colourless fluid, the titlecompound, are obtained: ¹H-NMR (CDCl₃): 1.15 (t, 3H); 2.53 (m, 4H); 3.24(s, 3H); 4.05 (q, 4H); 4.30 (quin., 1H); 4.58 (s, 2H).

[0101] b) Compound of Formula Cc wherein R=Ethyl,A=Methoxymethyl(monoethyl-3(R)-methoxymethoxyglutaric Acid):

[0102] 7.4 g of diethyl-3-methoxymethoxyglutaric acid Bc are suspendedat room temperature in 100 ml of distilled water, and 20 ml of 0.1Mphosphate buffer (pH 7) are added. After the addition of 1.0 g ofchymotrypsin, the mixture is stirred vigorously and maintained at pH 7.8using a pH meter and pH stat (Metrohm) and 0.5N sodium hydrogencarbonate solution.

[0103] When the theoretical amount of carbonate solution has beenconsumed, the mixture is extracted with ethyl acetate. The aqueous phaseis adjusted to pH 3-3.5 with 0.5N hydrochloric acid and then extractedwith ethyl acetate. Any cloudiness of the organic phase can be removedby filtration over Celite. After washing of the organic phase withsaturated sodium chloride solution and evaporation of the organic phase,5.4 g (82%/o) of spectroscopically clean monoacid, the tide compound,remain: ¹H-NMR (CDCl₃): 1.24 (t, 3H); 2.69 (m, 4H); 3.34 (s, 3H); 4.13(q, 2H); 4.38 (quin., 1H); 4.68 (s, 2H).

[0104] c) Determination of the Enantiomeric Excess (ee) of the MonoacidCc by Means of the Amide with Benzylamine:

[0105] 400 mg of the monoacid are reacted by customary methods forpeptide coupling with 760 mg of(benzotriazolyl-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 215 μl of Hünig's base and 0.70 ml of benzylamine(Fluka) in 2.0 ml of DMF at from 0° C. to room temperature. Aftercustomary extraction, 567 mg of amide are obtained. HPLC analysis(Chiralcel OD, 25×0.46 cm, n-hexane:ethanol=98:2, 1 ml/min) confirms aratio of R to S of more than 98:2. ¹H-NMR (CDCl₃): 1.19 (t, 3H), 2.48(dd, 2H); 2.56 (dd, 1H); 3.24 (s, 2H); 4.06 (broad q, 1H); 4.34 (m, 3H);4.59 (m, 2H); 7.00 (broad s, NH); 7.20 (m, 5H).

EXAMPLE 4

[0106] a) Precursor of Formula Bd wherein R=Ethyl,A=2-methoxyethoxymethyl(diethyl-3-(2-methoxyethyl)-oxymethoxyglutaricAcid):

[0107] At 0° C., 11.23 g of diethy-3-hydroxyglutaric acid A (Fluka) areintroduced together with 11.8 ml of diisopropylethylamine into 40 ml ofdichloromethane, and 8.6 g of 2-methoxyethoxymethyl chloride (Fluka) areadded. The mixture is stirred vigorously overnight, the temperature ofthe mixture rising to room temperature. The mixture is diluted withmethylene chloride and washed in succession with 2×1N hydrochloric acid,2×saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution. The organic phase is separated and dried overmagnesium sulfate. After evaporation of the solvent, a colourless liquidis obtained, 15.91 g (99%), the title compound. ¹H-NMR (CDCl₃): 1.20 (t,3H); 2.59 (m, 4H); 3.32 (s, 3H); 3.49 (m, 2H); 3.63 (m, 2H); 4.09 (q,4H); 4.36 (quin., 1H); 4.73 (s, 2H).

[0108] b) Compound of Formula Cd wherein R=Ethyl,A=2-methoxyethoxymethyl(monoethyl-3(R)-(2-methoxyethyl)-oxymethoglutaricAcid):

[0109] 7.4 g of diethyl-3-(2-methoxyethyl)-oxymethoxyglutaric acid Bdare suspended at room temperature in 30 ml of distilled water, and 3.3ml of 0.1M phosphate buffer (pH 7) are added. After the addition of 0.1g of chymotrypsin, the mixture is stirred vigorously and maintained atpH 7.8 using a pH meter and pH stat (Metrohm) and 0.5N sodium hydroxidesolution. When the theoretical amount of hydroxide solution has beenconsumed, the mixture is extracted with ethyl acetate. The aqueous phaseis adjusted to pH 3-3.5 with 0.5N hydrochloric acid and then extractedwith ethyl acetate. Any cloudiness of the organic phase can be removedby filtration over Celite. After washing of the organic phase withsaturated sodium chloride solution and evaporation of the organic phase,1.44 g (79%) of spectroscopically clean monoacid, the title compound,remain: ¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.02 (s, 3H); 2.67 (m, 4H); 3.38(s, 3H); 3.55 (m, 2H); 3.69 (m, 2H); 4.12 (q, 4H); 4.41 (quin., 1H);4.79 (q, 2H).

[0110] c) Determination of the Enantiomeric Excess (ee) of the MonoacidCc by Means of the Amide Dc ((R=Ethyl, A=2-methoxyethoxymethyl:

[0111] 380 mg of the monoacid Cd are reacted in accordance withcustomary methods for peptide coupling with 682 mg of(benzotriazolyl-1-yloxy)-tris(dimethylamino)phosphoniumhexafluorophosphate, 493 μl of Hünig's base and 185 μl ofR-phenylethylamine (Fluka) in 3.0 ml of DMF at from 0° C. to roomtemperature. After customary extraction, 403 mg of amide are obtained.NMR-spectroscopy indicates a diastereoisomeric ratio of greater than95:5 on the basis of the shift difference between the two methoxy groupsin the diastereoisomers. HPLC analysis (Chiralcel OD, 25×0.46 cm,n-hexane:ethanol=95:5, 1 ml/min) confirms the ratio of R to S as 98:2.¹H-NMR (CDCl₃): 1.22 (t, 3H), 1.45 (d, 3H); 2.48 (m, 2H); 2.62 (m, 2H);3.30 (s, ca. 5%); 3.38 (s, 95%); 3.50 (m, 4H); 4.12 (1, 1H); 4.34(quint., 1H); 4.79 (q, 2H); 5.11 (quint., 1H); 6.54 (broad d, NH), 7.34(m, 5H).

[0112] Reaction Scheme II for Examples 5 and 7 (the Radicals being asDefined in the Examples):

EXAMPLE 5 Glutaric Acid Semihalides of Formula 1

[0113] a) Monoethyl Ester of (3R)-acetoxy-glutaric Acid Chloride 1a(R=Ethyl, X=Cl. R′=Acetyl):

[0114] 30.0 g of (3R)-acetoxyglutaric acid monoethyl ester (Ca) aredissolved in 60 ml of dry dichloromethane to which 20 drops of dry DMFhave been added, and at 0-50° C. the solution is slowly treated with21.9 g of oxalyl chloride. The mixture is then stirred for about 30 min.at 0° C. and then for a further 1.5 h at room temperature until theevolution of gas can no longer be observed. After evaporation of thesolvent, 32.6 g of NMR-spectroscopically pure acid chloride 1a remain.(Colourless product can be obtained after molecular distillation).¹H-NMR (CDCl₃): 1.25 (t, 3H); 2.04 (s, 3H); 2.66 (dd, 1H); 2.70 (dd,1H); 3.30 (dd, 1H); 3.34 (dd, 1H); 4.16 (q, 2H); 5.47 (m, 1H).

[0115] b) Monoethyl Ester of (3R)-acetoxyglutaric Acid Bromide 1b(R=Ethyl, X═Br, R′=acetyl):

[0116] 5.0 g of (3R)-acetoxyglutaric acid monoethyl ester (Ca) aredissolved in 18 ml of dry dichloromethane to which a drop of dry DMF hasbeen added, and at 0-5° C. the solution is slowly treated with 6.7 g ofoxalyl bromide. The mixture is then stirred for about 30 min. at 0° C.and then for a further 2 h at room temperature until the evolution ofgas can no longer be observed. After evaporation of the solvent, 6.6 g(98%) of spectroscopically pure acid bromide 1b remain: ¹H-NMR (CDCl₃):1.21 (t, 3H); 2.00 (s, 3H); 2.62 (dd, 1H); 3.39 (dd, 1H); 3.42 (dd, 1H);4.11 (q, 2H); 5.41 (m, 1H).

[0117] c) Monoethyl Ester of (3R)-Methoxyacetoxyglutaric Acid Chloride1c (R=Ethyl, X═Cl. R′=Methoxyacetyl):

[0118] 21.0 g of monoethyl-3(R)-methoxyacetoxyglutaric add Cb aredissolved in 100 ml of dry dichloromethane to which 40 μl of dry DMF hasbeen added, and at 0-5° C. the solution is slowly treated with 13.9 g ofoxalyl chloride. The mixture is then stirred for about 4 h, thetemperature of the mixture rising to room temperature. The mixture isthen diluted with ethyl acetate and extracted 3× with ice-water, and theorganic phase is dried over sodium sulfate. After evaporation of thesolvent, 20.9 g of NMR-spectroscopically pure acid chloride 1c remain:¹H-NMR (CDCl₃): 1.20 (t, 3H); 2.04 (s, 3H); 2.67 (m, 2H); 3.32 (m, 2H);3.36 (s, 3H); 3.95 (s, 2H); 4.09 (q, 2H); 5.52 (m, 1H).

[0119] d) Monoethyl Ester of (3R)-Methoxymethoxyalutaric Acid ChlorideId (R=Ethyl, X═Cl, R′=methoxymethyl):

[0120] 0.40 g of the monoacid Cc is dissolved in 2 ml of drydichlromethane to which 3 drops of dry DMF are added, and at 0-5° C. thesolution is slowly treated with 0.18 ml of oxalyl chloride until theevolution of gas can no longer be observed. After evaporation of thesolvent, 0.43 g of acid chloride Id remains: ¹H-NMR (CDCl₃): 1.25 (t,3H); 2.67 (m, 4H); 3.69 (s, 3H); 4.13 (q, 2H); 5.53 (q, 1H); 5.54 (s,2H).

[0121] e) Monoethyl Ester of (3R)-(2-methoxyethyl)-oxymethoxyglutaricAcid Chloride Ie (R=ethyl, X═Cl, R′=2-methoxyethyloxymethyl):

[0122] 0.53 g of the monoacid Cd is dissolved in 2 ml of drydichloromethane to which 2 drops of dry DMF have been added, and at 0-5°C. the solution is slowly treated with 0.21 ml of oxalyl chloride untilthe evolution of gas can no longer be observed. After evaporation of thesolvent, 0.54 g of acid chloride 1e remains: ¹H-NMR (CDCl₃): 1.21 (t,3H); 2.55 (m, 1H); 2.65 (m, 1H); 3.24 (m, 2H); 3.34 (s, 3H); 3.50 (m,2H); 3.65 (m, 2H); 4.10 (q, 2H); 4.38 (quint., 1H); 4.74 (m, 2H).

EXAMPLE 6 Preparation of Compounds 11, 12, 13 and 5′

[0123] (i) (f) Preparation of 11a (R=Ethyl, R′=Acetyl. R*═H, R**═H)

[0124] 50 g of (3R)-acetoxyglutaric acid monomethyl ester monochloride1a are dissolved in 500 ml of tert-butyl methyl ether and at 0° C.treated with ammonia gas until the absorption of ammonia has ceased. Theprecipitated ammonium chloride is filtered off. After evaporation of thesolvent, 44.5 g (97%) of NMR-spectroscopically pure amide 11a remain:¹H-NMR (CDCl₃): 1.24 (t, 3H); 2.02 (s, 3H); 2.60 (dd, 2H); 2.72 (m, 2H);4.13 (q, 2H); 5.47 (m, 1H); 5.95 (s, br, 2H).

[0125] (ii) (f) Preparation of 11b (R=Ethyl, R=Acetyl. R*=Benzyl.R**=Benzyl)

[0126] At 0° C., a mixture of 41.7 g of dibenzylamine and 21.4 g oftriethylamine is slowly added dropwise to 50 g of (3R)-acetoxyglutaricacid monomethyl ester monochloride 1a in 250 ml of methylene chlorideand the mixture is stirred at room temperature for a further 2 h. Thereaction mixture is then washed with 100 ml of 0.1N HCl and 2×100 ml ofwater and the organic phase is dried over sodium sulfate. Afterevaporation of the solvent, 79.8 g (95%) of NMR-spectroscopically puredibenzylamide 2b remain: ¹H-NMR (CDCl₃): 1.24 (t, 3H); 1.99 (s, 3H);2.72 (m, 2H), 2.90 (m, 2H); 4.13 (qq, 2H); 4.48 (q, 2H); 4.55 (q, 2H),5.63 (m, 1H), 7.25 (m, 10H).

[0127] (iii) (f) Preparation of 11c (R=Ethyl, R═H. R*=Benzyl,R**=Benzyl)

[0128] 60 g of (3R)-acetoxyglutaric acid monoethyl estermono(N,N-dibenzyl)amide 11 b are stirred in 600 ml of 2M ethanolic HClat room temperature for 12 h. After evaporation of the solvent, 53.1 g(99%) of NMR-spectroscopically pure dibenzylamide 1 ic remain: ¹H-NMR(CDCl): 1.24 (t, 3H); 2.60 (m, 2H); 2.90 (m, 2H); 4.10 (q, 2H); 4.43 (m,2H), 4.50 (m, 1H), 4.55 (m, 2H), 7.25 (m, 10H).

[0129] (ix) (k) Preparation of 5′a (Ra=tert-butyl. R′ and R″Together=Isopropylidene)

[0130] Starting from 13, the amine 5′a is prepared by reduction withhydrogen in the presence of ammonia and a molybdenum-doped Raney nickelcatalyst in methanol (see Baumann, K. L-, et al., Tetrahedron Lett.33(17), 2283-2284 (1992)).

[0131] (x) (g) Preparation of 12a (Ra=Tert-butyl, R′═H. R*=Benzyl.R**=Benzyl

[0132] At −20° C., 500 ml of butyllithium (1.6M in hexane) are slowlyadded to 86.0 g of diisopropylamine in 200 ml of THF and the reactionmixture is stirred for a further 10 min. Then 92.8 g of tert-butylacetate are slowly added and stirring is continued for a further hour at−20° C. A solution of 71 g of 11c in 150 ml of THF is then slowly addedand the reaction mixture is stirred for a further 2 h at −20° C., thenslowly heated to room temperature and stirred for a further 2 h. 500 mlof 4N hydrochloric acid are then slowly added and the phases areseparated. The organic phase is washed with 2×′250 ml of saturatedsodium chloride solution and dried over sodium sulfate. Afterevaporation of the solvent, 85 g of crude dibenzylamine 12a remain:¹H-NMR (CDC): 1.46 (d,d, 9H); 2.55 (m, 2H); 3.39 (s, 2H); 4.42 (s, 2H);4.54 (m, 1H); 4.58 (s, 2H); 7.25 (m, 10H).

[0133] (xi) (h) Preparation of the Compound 13a (Ra=Tert-butyl, R′═H.R″═H, R*=benzyl, R**=Benzyl)

[0134] At −40° C., a solution of 18.6 g of 12a in 50 ml of THF is slowlyadded to a mixture of 130 ml of THF, 70 ml of methanol and 70 ml oftriethylborane (1M in THF) and the reaction mixture is cooled to −70° C.2.85 g of sodium borohydride are added in 5 portions and stirring iscontinued at −70° C. for a further 90 min. After the addition of 85 mlof 1M hydrochloric acid, the reaction mass is heated to roomtemperature. 100 ml of ethyl acetate and 10 g of sodium chloride areadded and the phases are separated. The organic phase is dried withsodium sulfate and the solvent is evaporated off. The residue is 5×taken up in 100 ml of methanol and concentrated by evaporation. 17.7 g(95%) of crude syndihydroxy-dibenzylamide 13a remain: ¹H-NMR (CDCl₃):1.46 (dd, 9H); 1.58 (m, 2H); 2.32 (m, 2H); 2.51 (m, 2H); 4.11 (m, 1H);4.20 (m, 1H); 4.35 (m, 2H); 4.51 (q, 2H); 7.25 (m, 10H).

[0135] (xii) (Conversion According to h) Preparation of 13b(Ra=Tert-butyl, R′ and R″ Together=Isopropaidene, R*=Benzyl, R**=Benzyl)

[0136] 17.0 g of crude 13a are dissolved in 50 ml of2,2-dimethoxypropane. After the addition of 0.2 ml of HCl (4M indioxane), the solution is stirred for 2 h at room temperature. Washingis then carried out with 50 ml of saturated sodium hydrogen carbonatesolution and the organic phase is dried over sodium sulfate. Afterevaporation of the solvent, 18.3 g (98%) of NMR-spectroscopically pureacetonide 13b remain: ¹H-NMR (CDCl₃): 1.27 (s, 3H); 1.36 (s, 9H); 1.38(m, 2H); 1.42 (s, 3H); 2.33 (m, 4H); 4.20 (m, 1H); 4.25 (dd, 2H); 4.44(m, 1H); 4.67 (dd, 2H); 7.25 (m, 10H).

[0137] (xiii) (i) Preparation of the Compound 5a (R_(a)=Tert-butyl, R′and R″ Together=Isopropylidene)

[0138] 30 ml of borane in THF (1M) are added to a solution of 4.7 g ofcrude 13b in 20 ml of THF and stirring is carried out for 1 h at roomtemperature. The solution is then heated to 40° C. and stirred for afurther 4 h. 20 ml of saturated sodium hydrogen carbonate solution isadded to the reaction solution and extraction is then carried out with20 ml of ethyl acetate. The organic phase is washed with 2×10 ml ofwater and dried over sodium sulfate. After evaporation of the solvent,the residue is taken up in 20 ml of ethanol and hydrogenated with 5%palladium on carbon at 55° C./20 bar. After the catalyst has beenfiltered off and the solvent evaporated, 1.8 g (67%) of crude amine 5aremain. The spectroscopic data correspond (except for the butyl radicalR_(a) which differs) to those of compound 5a.

[0139] (xiv) (i) Preparation of the Compound 5 (Ra=Tert-butyl, R′ and R″Together=Isopropylidene)

[0140] A solution of 1.52 kg of 13 in 2 It diglyme was charged into a 5l reactor. To this solution was added 246 g sodium borohydride. 0.781trimethyl silyl chloride was added slowly over a period of 1 hour. Thereaction mixture was diluted with 1 lt hexane. The resulting reactionmixture was slowly poored into a mixture of 2 It sodium hydrogenecarbonate and 2 It hexane. The reaction mixture was heated to reflux andstirred for an additional 2-3 hours. The reaction mixture was cooled toroom temperature and the 2 phases were separated. The hexane phase waswashed 4 times with 3 It water and stirred for 1 hour with 0.1 kg activecarbon. After filtration and evaporation of the solvent 1.3 kg of 5c

[0141] was obtained as a yellow oil and subsequently 1.3 kg of 5ccharged in a 5′lt autoclave with 2.7 lt methanol and 0.3 lt water andpurged with nitrogen. 62.5 g Pd—C were added and the autoclave waspurged 3 times with hydrogen followed by hydrogenation of the reactionmixture at 10 bar at a temperature of 70° C. for 3 hours. The catalystwas removed by filtration and the solvent was removed in vacuum leavinga cloudy residue. This residue is poured into a well stirred suspensionof 0.2 kg silica gel in 2.5 It heptane. This suspension is filteredafter 30 min and the filter cake is washed with heptane. This proceduregives 3.3 kg of a light yellow heptane solution, containing 460 gr 5a.

EXAMPLE 7 Further use of Compound 5 from Reaction Scheme II:

[0142] For the preparation of atorvastatin, a compound 5 is reacted witha compound of formula 17

[0143] analogously to the conditions described in WO 89/07598 for thereaction between that compound and a compound of formulaH₂N—CH₂CH₂—CH(OR₁₀)(OR₁₁), wherein R₁₀ and R₁₁, are alkyl having up to 8carbon atoms or together are 1,2-(1-methyl)ethylidene, 1,2-ethylidene or1,3-propylidene. Subsequent removal of protecting groups and, ifnecessary, opening of the lactone ring yields atorvastatin.

What is claimed is:
 1. A process for the preparation of the intermediate of formula VI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and R_(b) is a carboxy-protecting group, which is suitable for the preparation of statin derivatives, which process is carried out by conversion of the intermediate of formula XVI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group, R* and R** are each independently of the other hydrogen or an amide-protecting group, and R_(b) is a carboxy-protecting group; wherein compound of formula XVI is prepared by a process which comprises the preparation of a a compound of formula I

wherein X is halogen, acyloxy, activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH₃)—OCH₃, R_(a) is hydrogen or a hydroxy-protecting group and R_(b) is a carboxy-protecting group, wherein compound of formula I is prepared by conversion a compound of formula XI

wherein R_(a) is a hydroxy-protecting group and R_(b) is a carboxy-protecting group, into the corresponding compound of formula I using a reagent that introduces the radical X.
 2. A process according to claim 1, wherein the compound of formula XI is prepared by hydrolysing a compound of formula XII

wherein R_(a) is a hydroxy-protecting group, R_(b) is a carboxy-protecting group and R_(d) is hydrocarbyl, R_(b) and R_(d) preferably being identical, by means of an enantioselective catalyst, with removal of the radical R_(d), the corresponding compound of formula XI being obtained directly, the compound of formula XII in turn being obtained by reacting a glutaric acid derivative of formula XIII

wherein R_(b) and R_(d) are as defined for compounds of formula XII, by introduction of a hydroxy-protecting group using the corresponding reagent suitable for the introduction of the protecting group.
 3. A process, especially according to claim 1, comprise the conversion of a compound of formula I wherein X is halogen, acyloxy, activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH₃)OCH₃, R_(b) is hydrogen or a hydroxy-protecting group and R_(b) is a carboxy-protecting group into an amide of formula I*

wherein R_(c)′ is hydrogen or a hydroxy-protecting group, R_(b)′ is hydrogen or a carboxy-protecting group and R* and R** are each independently of the other hydrogen or an amide-protecting group, preferably alkyl or substituted alkyl; which compound can then be converted to compound of formula XVI already described above in claim 1; the conversion is carried out of formula I* wherein R_(b)′ is hydrogen (obtainable, if necessary, from the compound of formula I* wherein R_(b)′ is a hydroxy-protecting group, by removal of protecting groups) and R_(b)′, R* and R** are as defined for the compound of formula I*, preferably at least one of the radicals R* and R** being an amide-protecting group is converted by reaction in the presence of a strong base with a compound of formula XX

wherein R_(b) is a carboxy-protecting group, to form a compound of formula XV

wherein R* and R** are as defined for compounds of formula I*, R_(c)′ is hydrogen and R_(b) is a carboxy-protecting group; that compound is then reduced diastereoselectively to form a syn-diol of formula XVI

wherein R_(a)′ and R_(c)′ are hydrogen; or, after subsequent introduction of protecting groups, R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group, with the proviso that at least one of the radicals is such a protecting group, or R_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group; R* and R** are as defined for the compound of formula I*, preferably at least one of them being an amide-protecting group; and R_(b) is a carboxy-protecting group; the resulting compound of formula XVI is then converted into a compound of formula VI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxyl-protecting group, and R_(b) is a carboxy-protecting group, by reduction and removal of protecting groups R* and R**, if present; and in the processes mentioned above, at any stage, even where not explicitly mentioned, if necessary one or more or all of the protecting groups present in the compounds of formulae I*, I, VI, XI to XIII, XV, XVI and/or XX in question are removed or one or more or all of the functional groups that are not to participate in a reaction, or that would interfere with the reaction, are converted into protected groups by the introduction of suitable protecting groups (especially hydroxy-protecting groups and/or carboxy-protecting groups), and it being possible for the compounds of formulae I*, I, VI, XI to XIII, XV, XVI and/or XX, where salt-forming groups are present and the reaction in question is not impaired, also to be in salt form.
 4. A process, especially according to any of the preceding claims 1 to 3, which comprises the diastereoselective reduction of a compound of formula XV

wherein R* and R** are each independently of the other hydrogen or an amide-protecting group, R_(c)′ is hydrogen and R_(b) is a carboxy-protecting group, preferably R* and R** are benzyl, R_(c)′ is hydrogen and R_(b) is tert-butyl; a) with a mixture of triethylborane or diethylborane methoxide with sodium borhydride, or b) which reaction is carried out as homogeneous reduction with hydrogen in the presence of a homogeneous metal catalyst, or c) which reaction is carried out as heterogeneous reduction with hydrogen in the presence of a heterogeneous platinum catalyst with an alkali metal or an alkaline-earth metal salt, especially with an alkaline-earth metal salt, and more especially with magnesium acetate, to form a syn-diol compound of formula XVI

wherein R* and R** are benzyl, R_(c)′ is hydrogen and R_(b) is tert-butyl and R_(a) is hydrogen.
 5. A process, especially according to any of the preceding claim 4, which comprises a diastereoselective reduction of a coumpound of formula XV

wherein R* and R** are as defined for compounds of formula I*, R_(c)′ is hydrogen and R_(b) is a carboxy-protecting group, preferably wherein R* and R** are benzyl, R_(c)′ is hydrogen and R_(b) is tert-butyl; with hydrogen in the presence of a heterogeneous platinum catalyst on carbon and magnesium acetate.
 6. A compound of formula I*

wherein R_(c)′ is hydrogen or a hydroxy-protecting group, R_(b)′ is hydrogen or a carboxy-protecting group and R* and R** are each independently of the other hydrogen or phenyl-lower alkyl.
 7. A compound of formula I* according to claim 6 wherein R_(b)′ is hydrogen or lower alkanoyl, especially acetyl, or lower alkoxy-lower alkanoyl, especially methoxyacetyl; R_(b)′ is lower alkyl, especially ethyl; and R* and R** are either both hydrogen or both benzyl.
 8. A compound of formula XV

wherein R* and R** are as defined for compounds of formula I*, R_(c)′ is a hydroxy-protecting group or hydrogen and R_(b) is a carboxy-protecting group.
 9. A compound of formula XV according to claim 8 wherein R* and R** are each hydrogen or especially are both benzyl, R_(c)′ is lower alkanoyl, such as acetyl, lower alkoxy-lower alkyl, such as methoxyacetyl, or especially hydrogen and R_(b) is lower alkyl, especially tert-butyl.
 10. A compound of formula XVI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group, or R_(a)′ and R_(c)′ together are a bridging hydroxy-protecting group; R* and R** are hydrogen or phenyl-lower alkyl; and R_(b) is a carboxy-protecting group.
 11. A compound of formula XVI according to claim 10, wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen, lower alkanoyl, especially acetyl, or lower alkoxy-lower alkanoyl, especially methoxyacetyl, or R_(a)′ and R_(c)′ together are an isopropylidene protecting group; R* and R** are hydrogen or are especially both benzyl; and R_(b) is lower alkyl, especially tert-butyl.
 12. Use of the compounds and processes of any of the preceeding claims for the preparation of a compound of formula VI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and R_(b) is a carboxy-protecting group.
 13. Use of a compound of formula VI

wherein R_(a)′ and R_(c)′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and R_(b) is a carboxy-protecting group, for the preparation of Atorvastatin. 